Method of making 11 alpha-or 11 beta-hydroxy-18-nor-17-alpha-alkyl-17 beta-methylandrosta-4,13-diene-3-ones

ABSTRACT

A METHOD FOR MAKING COMPOUNDS OF THE FORMULA   3-(O=),11-(HO-),18-NOR,17-R-ANDROSTA-4,13-DIENE   BY REACTING THE CORRESPONDING 11-HYDROXY-17A-ALKYLANDROSTA-4-ENE-17B-OL--3-ONE WITH A CATALYTIC AMOUNT OF ETHYLENE GLYCOL AND P-TOLUENE SULFONIC ACID, THEREBY ASSURING KETALIZATION WHILE CAUSING REVERSE PINACOL REARRANGEMENT TO PRODUCE THE INTERMEDIATE 11-HYDROXY-18-NOR-17AALKYL - 17B-METHYLANDROSTA-5,13-DIENE-3-ETHYLENEKETAL AND HYDROLYZING THE INTERMEDIATE IN THE SOLUTION OF ACETONE, ETHANOL, OR METHANOL IN THE PRESENCE OF A CATALYTIC AMOUNT OF HCL IS DISCLOSED.

United States Patent 3,799,955 METHOD OF MAKING 11 ALPHA- OR 11 BETA- HYDROXY 18 NOR 17-ALPHA-ALKYL-17 lfiifir-METHYLANDROSTA 4,13 DlENE-3- Giovanni De Marchi and Carlo Scolastico, Milan, Italy, assignors to Laboratorio Prodotti Biologici Braglia S.p.A., Milan, Italy N0 Drawing. Filed Jan. 29, 1973, Ser. No. 327,772 Claims priority, application Italy, July 31, 1972, 27,685/72 Int. Cl. C07c 167/00 US. Cl. 260397.45 4 Claims ABSTRACT OF THE DISCLOSURE A method for making compounds of the formula by reacting the corresponding 1l-hydroxy-17a-alkylandrosta-4-ene-17/8-ol-3-one with a catalytic amount of ethylene glycol and p-toluene sulfonic acid, thereby assuring ketalization while causing reverse pinacol rearrangement to produce the intermediate 11-hydroxy-l8-nor-17ualkyl l7 8-methylandrosta-5,l3-diene-3-ethyleneketal and hydrolyzing the intermediate in a solution of acetone, ethanol, or methanol in the presence of a catalytic amount of HCl is disclosed.

This invention relates to a process for the preparation of 115 hydroxy or 11a-hydroxy-18-nor-l7a-alkyl-l7 8- methylandrosta-4,l3-diene-3-ones of the general formula:

in which R is an alkyl group, having 1 to 4 carbon atoms, or a vinyl or ethynyl group. The compounds prepared by the method of this invention are utilized as starting materials for the synthesis of the corresponding 2-formy1-18- nor 17a alkyl-17/3-methylandrosta-1,4,13-triene-3-ones, which possess a hydroxyl group in the 115 or 110: position. The said formyl compounds have utilities as taught in US. Pat. No. 3,694,470, granted Sept. 26, 1972 to Piero Gomarasca and Carlo Scolastico, and commonly assigned herewith.

In general, the llp-hydroxy or lla-hydroxy-lS-nor- 17a-alkyl-17fi-methylandrosta-4,l3-diene-3-one is prepared from the corresponding llfl-hydroxy or llu-hydroxy-17u-alkylandrosta-4-ene-17fi-ol-3-one by reverse pinacol rearrangement in an acid environment. In any case, such a process does not give optimal yield due to the fact that the modification of the desired structure is ac- 3,799,955 Patented Mar. 26, 1974 companied by a dehydration of the hydroxyl in position 11.

It has been found that this inconvenience can be mitigated by eifecting the reverse pinacol rearrangement, not on the 3-keto A -steroids but on the A -3-ethylene-ketals; in this manner, the operation can be carried out much more easily and in conditions that are much more mild, notably in the presence of much smaller quantities of acids, that is, in the same conditions in which one can successfully carry out the conversion of A -3-keto-steroids to A -ethyleneketals.

The process involved in the present invention is carried out in two steps; in the first step, there is simultaneously:

(a) a ketalization of A -3-ketosteroid, to A -3-alkylketal,

and,

(b) a reverse pinacol rearrangement, by means of which one passes from llfi-(or 11w) hydroxy-l7oL-alkylandrosta-4-ene-3-one [or Ila-(or 1lfl-)hydroxy-17a-alkylestosterone], to Ila-or 115-) hydroxy-18-nor-17or-alkyl- 17B-methylandrosta-3,l3-diene-3-ethyleneketal, by operating at the boiling point, in a solution of benzene or xylene, or preferably toluene, in the presence of ethylene glycol and a catalytic quantities of p-toluene sulfonic acid, in a period of time varying between 3 and 5 hours.

In the second step of hydrolysis is carried out on the ketalic group of compounds obtained in the first step, in a solution of acetone, of ethanol, or preferably of meth anol, in the presence of catalytic quantities of 1 N HCl at the boiling point: the hydrolysis takes place immediately.

The solution obtained is diluted with methylene chloride and washed with water; it is then evaporated and dried, and the residue of evaporation is crystallized in ethyl ether. A pure product is obtained. In this manner, it is possible to isolate lIB-(or llu-)-hydroxy-l8- nor-lh-alkyl-l7fl-methylandrosta-4,13-diene-3-ones, with optimum yield (about 83% for 1118, and about 85% for In practice, it is necessary however to take note that the operations described herein are particularly valid for compounds of the series of 11a-hydroxy-18-nor-17aalkylandrosta-5,13-diene-3-ethyleneketals, which may be isolated and separated by crystallization (e.g. in the case of Not-methyl derived from aqueous methanol). On the other hand, in the compounds of the llfl-hydroxy-lS-nor- 17a alkyl-17B-methylandrosta-5,13-diene-3-ethyleneketal series, the grouping of 3-ketal-A appears extremely unstable and, in attempts at crystallization, give rise to mixtures of 3-keto-A and 3-ketal-A As a result, in this case, the process described above does not take place, for the hydrolysis is immediate, manifesting itself immediately with the first slight traces of humidity.

The sensitivity of the products of the hydrolysis is such that, according to tests done on the subject, merely the acidity of certain solvents is sufiicient to permit a partial hydrolysis to take place.

This is the reason that the hydrolysis takes place immediately without crystallization of the products of the first step, in the case of these compounds of the llfi-hydroxy series. The best yield can be obtained by using a solution of ethylene glycol and using catalytic quantities of toluene sulfonic acid, operating directly on the A -3-ketosteroids. In this case, the reaction takes place much more rapidly (times varying between 15 and 30 minutes) and the results are better.

Using only ethylene glycol as a solvent, it is possible to produce the reaction in a single step, without first isolat- 3 ing the llocor 11/3-hydroxy-17,17-dimethyl-1S-norandrosta-5,13-diene-3-ethyleneketal, which, on the contrary, is hydrolyzed directly into lluor 1lfi-hydr0xy-17,17-dimethyl-13-norandrosta-4,13-diene-3-one.

The invention will be better understood by reading the following examples which are not to be considered limitmg.

EXAMPLE 1 1 1 a-hydroxy- 1 8 nor- 17, 17-dimethylandrosta-5, 1 3- diene-3-ethyleneketal A solution of 1 gram of 11a-hydroxy-l7-methyltestosterone in 50 ml. of toluene and 8 ml. of ethylene glycol is boiled for 3 hours, after addition of 40 mg. of p-toluene sulfonic acid, using a Marcusson device for eliminating the toluene-water azeotrope. The solution is then washed with a solution saturated with NaHCO then with water. The solution is dried on Na SO and evaporated at reduced pressure until desiccated.

The result is 1 gram of product which can be utilized directly for hydrolysis. Nevertheless, 100 mg. crystallized in a methanol-water environment, yields 85 mg. of 11ahydroxy-l8-nor-17,17-dimethylandrosta 5,13 diene-3- ethyleneketal, with a melting point of 170172 C.

[a] 108 (c.:1% in 001 for 0221 13103: Percent calculated :76.70, H:9.36 Percent obtained (3:76.67, H=9.60

EXAMPLE 2 1 lp-hydroxy-l 8-nor- 17, 17-dimethylandrosta-5,13- diene-B-ethyleneketal Forty mg. of p-toluene sulfonic acid is added to a solution of 1 g. of 11B-hydroxymethyltestosterone in 50 ml. of toluene and 8 ml. of ethylene glycol. After 4 hours of refluxing with agitation and elimination of the water-toluene azeotrope by means of a Marcusson device, the mixture is cooled to ambient temperature and washed with a saturated solution of NaHCO then with water.

The product thus obtained is dried on Na SO and the thin layer of evaporation residue is examined. The reaction mixture (0.995 g.) is seen to be composed of 70% of 11 3 hydroxy-l8-nor-17,17-dimethylandrosta-5,13-diene-3-ethyleneketal having a melting point of 130-132 C. and 30% of 1lfi-hydroxy-18-nor-17,17-dimethylandrosta- 4,13-diene-3-one, having a melting point of 179l80 C. [oz] +101 (c. :1% of dioxane).

The presence of the latter, as in the results obtained above, is due to the great ease of hydrolysis of llfi-hydroxy-l8-nor-17,17-dimethylandrosta-5,13-diene 3 ethyleneketal.

To augment the yield of the reaction, the mixture of 1lp-hydroxy-l8-nor-17,17-dimethylandrosta 5,13 diene- 3-ethyleneketal and of 1lfi-hydroxy-l8-nor-17,17-dimethylandrosta-4,13-diene 3 one should be immediately subjected to hydrolysis.

EXAMPLE 3 1lp-hydroxy-l8-nor-17,17-dimethylandrosta-4,13- diene-3-one 0.2 ml. of 1 N hydrochloric acid is added to a solution of 1 g. of 1la-hydroxyd8-nor-17,17-dimethylandrosta-5, 13-diene-3-ethyleneketal in ml. of methanol and heated for 10 minutes. The solution is diluted with 40 ml. of methylene chloride, washed with 30 ml. of water, dried on Na SO and taken to dryness.

The product is crystallized from ethyl ether and there is obtained 0.850 g. with a melting point of 164-166 C. [u] +86 (c.:1% dioxane).

U.V.= (methanol) at 240 m (e=15780) I.R.:bands at 3410, 1658, 1610 cmr In the analysis for c H O' z Calculated: Percent 0:79.96, H=9.40 Obtained: Percent 0:79.90, H=9.44

/ EXAMPLE4 1 1p-hydroxy-18-nor-17,17-dimethylandrosta- 4,13-diene-3-one Following a procedure analogous to that described in Example 3, with 1 g. of a mixture of 11/3-hydroxy-l8-nor- 17,17-dimethylandrosta 5,13 diene-3-one and llp-hydroxy-l 8-nor-17,l7-dimethylandrosta-4,13-diene 3 one, there is obtained 0.830 g. of 11/3-hydroxy-18-nor-17,17- dimethylandrosta-4,l3-diene-3-one with a melting point of 179180 C. [a] ":101 (c.:1% dioxane).

U.V.: (methanol) at 240 my (e=15240) I.R.:b ands at 3390, 1650, 1612 cmr In the analysis for C H 'O Calculated: Percent 0:79.60, H:9.40 Obtained: Percent 0:79.80, H=9.53.

EXAMPLE 5 1 1ot-hydroxy-18-nor-17, 17-dimethylandrosta- 4,13-diene-3-one 40 mg. of p-toluene sulfonic acid was added to a solution of 1 g. of 1la-hydroxy-17-methyltestosterone in 10 m1. of anhydrous ethylene glycol.

The mixture is agitated for 20 minutes at 140 C., 'and then the temperature is lowered to C. and 1 ml. of 1 N HCl was added. After 15 minutes of agitation at that temperature, the solution is poured into a mixture of ice and salt. The solid thus formed is filtered, washed with water, melted in 15 ml. of methylenechloride, dried on Na SO and evaporated in a vacuum. The residue of the evaporation, crystallized in ethyl ether, gives 0.9 g. of 1lot-hydroxy-18-nor-17,17-dimethylandrosta 4,13 diene- 3-one; melting point of 164-166 C.

In the analysis for C H O Calculated: Percent 0:79.96, H=9.40 Obtained: Percent 0:79.85, H=9.43.

EXAMPLE 6 1 1 p-hydroxy- 1 8-nor-17, 17 dimethylandrosta- 4,13-diene-3-one Operating in the same fashion on up hydroxy 17- methyltestosterone, there is obtained llfl-hydroxy-18-nor- 17,91 7-dimethy1androsta-4,13-diene-3-one with a. yield of 93 0.

What is claimed is:

1. Process for the preparation of l1-hydroxy-18-nor- 17a-alkyl-17fl-methylandrosta-4,13-diene 3 one having the general formula:

wherein R is an alkyl group having 1 to 4 carbon atoms, a vinyl group, or an ethynyl group, and said ll-hydroxy group is in the or the llfl-position, said process comprising the steps of:

(a) reacting 11- or 1lp-hydroxy-17a-a1kylandrosta-4- ene-17fl-ol-3-one with a catalytic amount of ethylene glycol and p-toluene sulfonic acid at the boiling point, thereby assuring ketalization while simultaneously causing reverse pinacol rearrangement, to thereby produce the intermediate product llczor llfl-hydroxy-18-nor-17a-alkyl 17p methylandrosta-5,13- diene-3-ethyleneketal; and

5 6 (b) hydrolyzing said intermediate product in a solution References Cited of acetone, ethanol, or methanol, in the presence of a catalytic amount of HCl at the boiling point. UNITED STATES PATENTS The Process of claim 1, wherein p is p 3,694,470 9/1972 Gomarasca et a1. 260397.45 formed in a solvent of benzene, xylene, or toluene. 5

3. The process of claim 2, wherein said solvent is HENRY A. FRENCH, {Primary Examiner toluene.

4. The process of claim 1, wherein the solvent in step US. Cl. X.R. (b) is methanol. 260239.55 C 

